1. Field of the Invention
This invention relates to isoquinolinamine and phthalazinamine derivatives which selectively bind to corticotropin-releasing factor (CRF) receptors. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating stress related disorders such as post traumatic stress disorder (PTSD) as well as depression, headache and anxiety.
2. Description of the Related Art
Isoquiolinamines and phthalazinamines have been described in the prior art. For example, Sindler-Kulyk et al, J. Org. Chem., 48(8), 1275-81, (1983) describe a 1-phenyl-4-isoquinolinamine. British Patent GB 1303061 disclose aminophthalazines said to have antiinflammatory activity. Holava et al., J. Med. Chem., 12, 555-6, (1969), describe a 4-phenyl-1-phthalazinamine.
This invention provides novel compounds of Formula I which interact with CRF receptors.
The invention provides pharmaceutical compositions comprising compounds of Formula I. It further relates to the use of such compounds in treating stress related disorders such as post traumatic stress disorder (PTSD) as will as depression, headache and anxiety. Accordingly, a broad embodiment of the invention is directed to a compound of Formula I: 
wherein
Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4pyridinyl, 2- or 3thienyl, 4- or 5pyrimidinyl, each of which is mono-, di-, or trisubstituted with halogen, hydroxy, C1-C6 alkyl, or C1-C6 alkoxy, with the proviso that at least one of the positions on Ar ortho to the point of attachment to the phthalazinamine or isoquinolinamine ring is substituted;
R1 and R2 are the same or different and represent
hydrogen, C1-C6 alkyl, halogen, hydroxy, C1-C6 alkoxy,
NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NO2, cyano, trifluoromethyl;
R3 and R4 are the same or different and represent
hydrogen, C1-C6 alkyl optionally substituted with halogen, hydroxy, or C1-C6 alkoxy; or
aryl(C1-C6)alkyl, where aryl is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl or 2-, 4-, or 5-pyrimidinyl, each of which is optionally mono- or disubstituted with halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy; or C1-C6 alkyl-Yxe2x80x94R5, wherein Y is O, S NH, N(C1-C6 alkyl), and R5 is hydrogen or C1-C6 alkyl; and
W is N or Cxe2x80x94R6, where in R6 is hydrogen or C1-C6 alkyl.
These compounds are highly selective partial agonists or antagonists of CRF receptors and are useful in the diagnosis and treatment of stress related disorders such as post traumatic stress disorder (PTSD) as well as depression and anxiety.
The invention further encompasses methods for treating mammals, such as, for example, humans and companion animals (i.e., cats and dogs) suffering from PTSD, depression, and/or anxiety. Such methods comprise administering to a patient mammal an amount effective of a compound of Formula I to relieve the depression, anxiety or PTSD.
In addition to the compounds of Formula I above, the invention provides compounds encompassed by Formula II: 
wherein
Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is mono-, di-, or trisubstituted with halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy with the proviso that at least one of the positions on Ar ortho to the point of attachment to the phthalazinamine ring is substituted;
R1 and R2 are the same or different and represent hydrogen, C1-C6 alkyl, halogen, hydroxy, C1-C6 alkoxy, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NO2, cyano, trifluoromethyl; and
R3 and R4 are the same or different and represent
hydrogen, C1-C6 alkyl optionally substituted with halogen, hydroxy, or C1-C6 alkoxy; or
aryl(C1-C6)alkyl, where aryl is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl or 2-, 4-, or 5-pyrimidinyl, each of which is optionally mono- or disubstituted with halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy; or C1-C6 alkyl-Yxe2x80x94R5, wherein Y is O, S NH, N(C1-C6 alkyl), and R5 is hydrogen or C1-C6 alkyl.
In preferred compounds of Formula II, R3 and R4 are not both hydrogen simultaneously. Preferred compounds of formula II are those where R3 and R4 independently represent C1-C6 alkyl optionally substituted with halogen, hydroxy, or C1-C6 alkoxy, Ar is phenyl that is mono-, di-, or trisubstituted with halogen, hydroxy, C1-C6 alkyl, or C1-C6 alkoxy, with the proviso that at least one of the positions on the phenyl group ortho to the point of attachment to the phthalazinamine ring is substituted. More preferred compounds of Formula II are those where R1 and R2 are independently hydrogen or lower alkyl, most preferably hydrogen or C1-C3 alkyl; and Ar is phenyl that is trisubstituted with C1-C6 alkyl, with the proviso that at least one of the positions on the phenyl group ortho to the point of attachment to the phthalazinamine ring is substituted. Most preferred compounds of Formula II are those where R1 and R2 are hydrogen; and R3 and R4 independently represent C1-C6 alkyl optionally substituted with halogen, hydroxy, or C1-C6 alkoxy, Ar is phenyl that is trisubstituted in the 2, 4, and 6 positions (para and both ortho positions relative to the point of attachment to the phthalazinamine ring) with C1-C3 alkyl, most preferably methyl. Particularly preferred compounds of Formula II are those where R3 and R4 are independently hydrogen or C1-C4 alkyl, e.g., methyl, ethyl, propyl, butyl, or cyclopropylmethyl, provided that not both R3 and R4 are hydrogen simultaneously.
The invention also provides compounds of formula III: 
wherein
Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is mono-, di-, or trisubstituted with halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy with the proviso that at least one of the positions on Ar ortho to the point of attachment to the phthalazinamine ring is substituted; and
R3 and R4 are the same or different and represent
hydrogen, C1-C6 alkyl optionally substituted with halogen, hydroxy, or C1-C6 alkoxy; or
aryl(C1-C6)alkyl, where aryl is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl or 2-, 4-, or 5-pyrimidinyl, each of which is optionally mono- or disubstituted with halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy; or C1-C6 alkyl-Yxe2x80x94R5, wherein Y is O, S NH, N(C1-C6 alkyl), and R5 is hydrogen or C1-C6 alkyl.
In preferred compounds of Formula III, R3 and R4 are not both hydrogen simultaneously. Preferred compounds of formula III are those where R3 and R4 independently represent C1-C6 alkyl optionally substituted with halogen, hydroxy, or C1-C6 alkoxy, Ar is phenyl that is mono-, di-, or trisubstituted with halogen, hydroxy, C1-C6 alkyl, or C1-C6 alkoxy, with the proviso that at least one of the positions on the phenyl group ortho to the point of attachment to the phthalazinamine ring is substituted. Most preferred compounds of Formula III are those where R3 and R4 independently represent C1-C6 alkyl optionally substituted with halogen, hydroxy, or C1-C6 alkoxy, Ar is phenyl that is trisubstituted in the 2, 4, and 6 positions (para and both ortho positions relative to the point of attachment to the phthalazinamine ring) with C1-C3 alkyl, most preferably methyl. Particularly preferred compounds of Formula III are those where R3 and R4 are independently hydrogen or C1-C4 alkyl, e.g., methyl, ethyl, propyl, butyl, or cyclopropylmethyl, provided that not both R3 and R4 are hydrogen simultaneously.
The invention provides compounds of formula IV 
wherein
Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is mono-, di-, or trisubstituted with halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy with the proviso that at least one of the positions on Ar ortho to the point of attachment to the isoquinolinamine ring is substituted;
R1 and R2 are the same or different and represent hydrogen, C1-C6 alkyl, halogen, hydroxy, C1-C6 alkoxy, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NO2, cyano, trifluoromethyl;
R3 and R4 are the same or different and represent
hydrogen, C1-C6 alkyl optionally substituted with halogen, hydroxy, or C1-C6 alkoxy; or
aryl(C1-C6)alkyl, where aryl is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl or 2-, 4-, or 5-pyrimidinyl, each of which is optionally mono- or disubstituted with halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy; or C1-C6 alkyl-Yxe2x80x94R5, wherein Y is O, S NH, N(C1-C6 alkyl), and R5 is hydrogen or C1-C6 alkyl; and
R6 is hydrogen or C1-C6 alkyl.
In preferred compounds of Formula IV, R3 and R4 are not both hydrogen simultaneously. Preferred compounds of Formula IV are those where R3 and R4 independently represent C1-C6 alkyl optionally substituted with halogen, hydroxy, or C1-C6 alkoxy, Ar is phenyl that is mono-, di-, or trisubstituted with halogen, hydroxy, C1-C6 alkyl, or C1-C6 alkoxy, with the proviso that at least one of the positions on the phenyl group ortho to the point of attachment to the isoquinolinamine ring is substituted. Most preferred compounds of Formula IV are those where R3 and R4 independently represent C1-C6 alkyl optionally substituted with halogen, hydroxy, or C1-C6 alkoxy, Ar is phenyl that is trisubstituted in the 2, 4, and 6 positions (para and both ortho positions relative to the point of attachment to the isoquinolinamine ring) with C1-C3 alkyl, most preferably methyl. Particularly preferred compounds of Formula IV are those where R3 and R4 are independently hydrogen or C1-C4 alkyl, e.g., methyl, ethyl, propyl, butyl, or cyclopropylmethyl, provided not both R3 and R4 are hydrogen simultaneously.
The invention also provides compounds of formula V: 
wherein
Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is mono-, di-, or trisubstituted with halogen, hydroxy, C1-C6 alkyl, Cl-C6 alkoxy with the proviso that at least one of the positions on Ar ortho to the point of attachment to the isoquinolinamine ring is substituted;
R3 and R4 are the same or different and represent
hydrogen, C1-C6 alkyl optionally substituted with halogen, hydroxy, or C1-C6 alkoxy; or
aryl(C1-C6)alkyl, where aryl is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl or 2-, 4-, or 5-pyrimidinyl, each of which is optionally mono- or disubstituted with halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy; or C1-C6 alkyl-Yxe2x80x94R5, wherein Y is O, S NH, N(C1-C6 alkyl), and R5 is hydrogen or C1-C6 alkyl; and
R6 is hydrogen or C1-C6 alkyl.
In preferred compounds of Formula V, R3 and R4 are not both hydrogen simultaneously. Preferred compounds of formula V are those where R3 and R4 independently represent C1-C6 alkyl optionally substituted with halogen, hydroxy, or C1-C6 alkoxy, Ar is phenyl that is mono-, di-, or trisubstituted with halogen, hydroxy, C1-C6 alkyl, or C1-C6 alkoxy, with the proviso that at least one of the positions on the phenyl group ortho to the point of attachment to the isoquinolinamine ring is substituted. Most preferred compounds of Formula V are those where R3 and R4 independently represent C1-C6 alkyl optionally substituted with halogen, hydroxy, or C1-C6 alkoxy, Ar is phenyl that is trisubstituted in the 2, 4, and 6 positions (para and both ortho positions relative to the point of attachment to the isoquinolinamine ring) with C1-C3 alkyl, most preferably methyl. Particularly preferred compounds of Formula V are those where R3 and R4 are independently hydrogen or C1-C4 alkyl, e.g., methyl, ethyl, propyl, butyl, or cyclopropylmethyl, provided not both R3 and R4 are hydrogen simultaneously.
The invention also encompasses intermediates for preparing compounds of Formula I. Among these intermediates are compounds of Formula VI: 
wherein
X is NH2 or NO2;
R1, R2, and R6, are as defined above for Formula I;
Ra is hydrogen or RbO2Cxe2x80x94 where Rb represents C1-C6 alkyl; and
Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is mono-, di-, or trisubstituted with halogen, hydroxy, C1-C6 alkyl, or C1-C6 alkoxy, with the proviso that at least one of the positions on Ar ortho to the point of attachment to the isoquinolinamine ring is substituted.
Preferred Ar groups are 2,4,6-tri(C1-C6)alkylphenyl groups, most preferably 2,4,6-trimethylphenyl.
The invention further encompasses intermediates of Formula VII: 
wherein
X is NH2 or NO2;
R1, R2, and R6, are as defined above for Formula I;
Ra is hydrogen or RbO2Cxe2x80x94 where Rb represents C1-C6 alkyl; and
Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is mono-, di-, or trisubstituted with halogen, hydroxy, C1-C6 alkyl, or C1-C6 alkoxy, with the proviso that at least one of the positions on Ar ortho to the point of attachment to the isoquinolinamine ring is substituted.
Preferred Ar groups are 2,4,6-tri(C1-C6)alkylphenyl groups, most preferably 2,4,6-trimethylphenyl.
The invention further encompasses intermediates of Formula VIII: 
wherein
R1, R2, R3, and R6, are as defined above for Formula I; and Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is mono-, di-, or trisubstituted with halogen, hydroxy, C1-C6 alkyl, or C1-C6 alkoxy, with the proviso that at least one of the positions on Ar ortho to the point of attachment to the isoquinolinamine ring is substituted.
Preferred Ar groups are 2,4,6-tri(C1-C6)alkylphenyl groups, most preferably 2,4,6-trimethylphenyl.
Also encompassed by the invention are intermediates useful for preparing phthalazinamines of the invention. Thus, compounds of Formula IX are within the invention: 
wherein
R1, and R2 are as defined above for Formula I; and
Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is mono-, di-, or trisubstituted with halogen, hydroxy, C1-C6 alkyl, or C1-C6 alkoxy, with the proviso that at least one of the positions on Ar ortho to the point of attachment to the benzene ring is substituted.
Preferred Ar groups are 2,4,6-tri(C1-C6)alkylphenyl groups, most preferably 2,4,6-trimethylphenyl groups.
The invention also encompasses compounds of Formula X: 
R1, and R2 are as defined above for Formula I; and
Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is mono-, di-, or trisubstituted with halogen, hydroxy, C1-C6 alkyl, or C1-C6 alkoxy, with the proviso that at least one of the positions on Ar ortho to the point of attachment to the phthalazinone ring is substituted.
Preferred Ar groups are 2,4,6-tri(C1-C6)alkylphenyl groups, most preferably 2,4,6-trimethylphenyl.
The invention also encompasses compounds of Formula XI: 
R1 and R2 are as defined above for Formula I;
Y is a halogen, preferably chloride or bromide; and
Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl, 4- or 5-pyrimidinyl, each of which is mono-, di-, or trisubstituted with halogen, hydroxy, C1-C6 alkyl, or C1-C6 alkoxy, with the proviso that at least one of the positions on Ar ortho to the point of attachment to the phthalazinamine ring is substituted.
Preferred Ar groups are 2,4,6-tri(C1-C6)alkylphenyl groups, most preferably 2,4,6-trimethylphenyl.
Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to the compounds in Table I and their pharmaceutically acceptable salts. Non-toxic pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOCxe2x80x94(CH2)nxe2x80x94COOH where n is 0-4, and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.
The present invention also encompasses the acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.
When a compound of formula I is obtained as a mixture of enantiomers these may be separated by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, for example, using a chiral HPLC column.
In the compounds of the invention, the Ar group is preferably a phenyl group that is mono-, di-, or trisubstituted with halogen, hydroxy, C1-C6 alkyl, or C1-C6 alkoxy, with the proviso that at least one of the positions on the phenyl group ortho to the point of attachment to the isoquinolinamine or phthalazinamine ring is substituted. Where Ar is phenyl, the carbon atom by which the phenyl group is attached to the isoquinolinamine or phthalazinamine ring is defined as the 1-position. Thus, the positions ortho to the point of attachment are the 2 and 6 positions, and the para position is the 4-position of the phenyl group.
By the terms (C1-C6)alkyl and lower alkyl is meant straight and branched chain alkyl groups having from 1-6 carbon atoms as well as cyclic alkyl groups such as, for example, cyclopropyl, cyclobutyl, or cyclohexyl. Specific examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, neopentyl and n-pentyl. Preferred C1-C6 alkyl groups are methyl, ethyl, propyl, butyl or cyclopropylmethyl.
By the terms (C1-C6)alkoxy and lower alkoxy is meant, straight and branched chain alkoxy groups having from 1-6 carbon atoms.
By hydroxy C1-C6 alkyl is meant a C1-C6 alkyl group carrying a terminal hydroxy moiety.
By C1-C6 alkoxy C1-C6 alkyl is meant a group of the formula xe2x80x94(CH2)xO(CH2)yCH3, where x and y independently represent integers of from 1-6.
By the term C1-C6 alkenyl is meant straight or branched chain hydrocarbon groups having from 1-6 carbon atoms and at least one double bond.
By halogen, halo, or halide is meant fluorine, chlorine, bromine and iodine substituents.
By aryl(C1-C6)alkyl is meant aryl groups attached to the parent group by a straight or branched chain alkyl group having 1-6 carbon atoms. The aryl groups include phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridinyl, 2- or 3-thienyl or 2-, 4-, or 5-pyrimidinyl and are optionally substituted with up to two groups selected from halogen, hydroxy, (C1-C6 )alkyl, and (C1-C6)alkoxy.
Representative examples of compounds according to the invention are shown in Table 1 below.
The pharmaceutical utility of compounds of this invention are indicated by the following assay for CRF receptor activity.
Assay for CRF Receptor Binding Activity
CRF receptor binding is performed using a modified version of the assay described by Grigoriadis and De Souza (Biochemical, Pharmacological, and Autoradiographic Methods to Study Corticotropin-Releasing Factor Receptors. Methods in Neurosciences, Vol. 5, 1991). Membrane pellets containing CRF receptors are resuspended in 50 mM Tris buffer pH 7.7 containing 10 mM MgCl2 and 2 mM EDTA and centrifuged for 10 minutes at 48000 g. Membranes are washed again and brought to a final concentration of 1500 mg/ml in binding buffer (Tris buffer above with 0.1% BSA, 15 mM bacitracin and 0.01 mg/ml aprotinin.). For the binding assay, 100 ml of the membrane preparation is added to 96 well microtube plates containing 100 ml of 125I-CRF (SA 2200 Ci/mmol, final concentration of 100 pM) and 50 ml of drug. Binding is carried out at room temperature for 2 hours. Plates are then harvested on a Brandel 96 well cell harvester and filters are counted for gamma emissions on a Wallac 1205 Betaplate liquid scintillation counter. Non specific binding is defined by 1 mM cold CRF. IC50 values are calculated with the non-linear curve fitting program RS/1 (BBN Software Products Corp., Cambridge, Mass.).
The compounds of the invention typically have binding affinities, expressed as IC50 values, of from about 0.5 nanomolar (nM) to about 10 micromolar (xcexcM).
The compounds of general formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general formula I and a pharmaceutically acceptable carrier. One or more compounds of general formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, For example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of general formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
Compounds of general formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
A representative illustration of methods suitable for the preparation of compounds of the present invention is shown in Schemes I and II. Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention. For example, in certain situations, protection of reactive moieties such as amino groups, will be required. 
wherein Ar, R1, R2, R3, R4, and R6 are as defined as above for Formula I. 
In the above scheme, R1-R4, R6, W and Ar carry the definitions set forth above for Formula I.
The disclosures in this application of all articles and references, including patents, are incorporated herein by reference.